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BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Purpose To define the burden of morbidity and mortality arising from COVID-19 in individuals with primary (PID) and secondary immunodeficiency (SID) in the United Kingdom. Methods In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. Anonymised demographic data, pre-SARS-CoV-2 infection lymphocyte counts, co-morbidities, targeted treatments and outcomes were collected. Three groups were analysed in further detail: individuals with common variable immunodeficiency (CVID), individuals with any PID, including CVID, receiving immunoglobulin replacement therapy (IgRT) and individuals with secondary immunodeficiency. Results A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within the cohort was 17.7% (n = 55/310). Individuals with CVID demonstrated an infection fatality rate (IFR) of 18.3% (n = 17/93), individuals with PID receiving IgRT had an IFR of 16.3% (n = 26/159) and individuals with SID, an IFR of 27.2% (n = 25/92). Individuals with PID and SID, had higher inpatient mortality and died at a younger age than the general population. Increasing age, low pre-SARS-CoV-2 infection lymphocyte count and the presence of common co-morbidities increased the risk of mortality in PID. Access to specific COVID-19 treatments in this cohort was limited: only 22.9% (n = 33/144) of patients admitted to hospital received dexamethasone, remdesivir, an anti-SARS-CoV-2 antibody-based therapeutic (e.g. REGN-COV2 or convalescent plasma) or tocilizumab as a monotherapy or in combination. Dexamethasone, remdesivir and anti-SARS-CoV-2 antibody-based therapeutics appeared efficacious in PID and SID. Conclusion Compared to the general population, individuals with PID or SID are at high risk of mortality following SARS-CoV-2 infection. Increasing age, low baseline lymphocyte count and the presence of co-morbidities are additional risk factors for poor outcome in this cohort.

Needlestick injuries (NSIs) are one of the most serious occupational hazards for healthcare workers (HCWs).The aim of this study was to evaluate the incidence and causes of NSIs globally.A systematic review and meta-analysis of data from January 2000 to May 2020 collected from Scopus, PubMed, Embase, Web of Science, and Google Scholar. The Newcastle-Ottawa Scale was used to assess the quality of the included articles. The data obtained were analysed by R version 3/5/0, and 113 articles were retrieved.There were 113 studies with a total of 525 798 HCWs. The incidence of NSIs was 43%. Africa had the highest rate of these injuries of 51%, and the World Health Organization (WHO) African Region had the highest incidence among WHO regions of 52%. Women were more frequently affected by NSIs than men. Hepatitis C virus infection was the disease most commonly transmitted via NSIs (21%). The highest rates of NSIs according to causes, devices, hospital locations, occupations and procedures were for recapping of needles, needles, general wards, nurses and waste disposal, respectively.The incidence of NSIs is gradually decreasing. The findings of this study can contribute to improving the decision-making process for reducing NSIs in HCWs.معدل الإصابة بالإصابات الناجمة عن وخز الإبر وأسبابها على الأصعدة العالمية والإقليمية والوطنية: استعراض منهجي وتحليل تلوي.زهرة حسيني بالانجي، زهرة غول محمدي، أحمد غاشجي، نيلوفار أحمدي، حسين حسيني فارد، زهرة مجاري، أفسانه دهند، زبيدة أغالو، عزت جعفر جلال، أيدن أريانخيسال، سيما الرافعي، أناهيتا خاجيهفاند، محمد ناساب، فاطمة باشا زاده كان.تُعد الإصابات الناجمة عن وخز الإبر واحدة من أكبر المخاطر المهنية التي تواجه العاملين في مجال الرعاية الصحية.هدفت هذه الدراسة إلى تقييم معدل الإصابة بالإصابات الناجمة عن وخز الإبر وأسبابها على الصعيد العالمي.استعراض منهجي وتحليل تلوي للبيانات الواردة في الفترة من يناير/ كانون الثاني 2000 إلى مايو/ أيار 2020 التي جُعت من قواعد البيانات Scopus وPubMed وEmbase وWeb of Science وGoogle Scholar. واستُخدم مقياس نيوكاسل-أوتاوا لتقييم جودة المقالات الواردة في قواعد البيانات. وخضعت البيانات التي جُعت للتحليل بواسطة النسخة 3/5/0 من برنامج R، واعتمدت الدراسة على 113 مقالً.كانت هناك 113 دراسة شملت ما مجموعه 525798 عاملً في مجال الرعاية الصحية. وبلغ معدل الإصابة بالإصابات الناجمة عن وخز الإبر 43٪. وسجَّلت أفريقيا أعلى معدل لهذه الإصابات بنسبة 51٪، بينما سجَّل الإقليم الأفريقي لمنظمة الصحة العالمية أعلى معدل للإصابة بين أقاليم المنظمة بنسبة 52٪. وكانت النساء أكثر تضررًا من الإصابات الناجمة عن وخز الإبر من الرجال. وكانت العدوى بفيروس التهاب الكبد C هي المرض الأكثر شيوعًا المنقول بوخز الإبر (21٪). وكانت أعلى معدلات الإصابات الناجمة عن وخز الإبر حسب الأسباب، والأجهزة، والمواقع داخل المستشفيات، والمهن، والإجراءات هي إعادة تغطية الإبر، والإبر، والأجنحة العامة، وطواقم التمريض، والتخلص من النفايات على التوالي.يتناقص معدل الإصابة بالإصابات الناجمة عن وخز الإبر تدريجيًّا. ويمكن أن تسهم نتائج هذه الدراسة في تحسين عملية اتخاذ القرار للحد من الإصابات الناجمة عن وخز الإبر في صفوف العاملين في مجال الرعاية الصحية.Incidence et causes des blessures par piqûre d'aiguille aux niveaux mondial, régional et national : revue systématique et méta-analyse.Les blessures par piqûre d'aiguille constituent l'un des risques professionnels les plus graves pour les agents de santé.L'objectif de la présente étude était d'évaluer l'incidence et les causes des blessures par piqûre d'aiguille à l'échelle mondiale.Nous avons réalisé une analyse systématique et une méta-analyse des données recueillies dans Scopus, PubMed, Embase, Web of Science et Google Scholar de janvier 2000 à mai 2020. L'échelle de Newcastle-Ottawa a été utilisée pour évaluer la qualité des articles inclus. Les données obtenues ont été analysées au moyen du logiciel R version 3/5/0 et 113 articles ont été récupérés.Il y avait 113 études incluant un total de 525 798 agents de santé. L'incidence des blessures par piqûre d'aiguille était de 43 %. Le continent africain affichait le taux le plus élevé de ces traumatismes, soit 51 %, tandis que la Région africaine de l'Organisation mondiale de la Santé (OMS) présentait l'incidence la plus élevée parmi les régions de l'OMS, soit 52 %. Les femmes étaient plus souvent touchées par les blessures par piqûre d'aiguille que les hommes. L'infection par le virus de l'hépatite C était la maladie la plus souvent transmise par les blessures par piqûre d'aiguille (21 %). Les taux les plus élevés de blessures par piqûre d'aiguille selon les causes, les dispositifs, les sites hospitaliers, les professions et les procédures concernaient respectivement le recapuchonnage des aiguilles, les aiguilles, les services de médecine générale, les personnels infirmiers et l'élimination des déchets.L'incidence des blessures par piqûre d'aiguille diminue progressivement. Les résultats de la présente étude peuvent contribuer à améliorer le processus de prise de décision pour la réduction des blessures par piqûre d'aiguille chez les agents de santé.

Chronic pain has widespread, detrimental effects on the human nervous system and its prevalence and burden increase with age. Machine learning techniques have been applied on brain images to produce statistical models of brain aging. Specifically, the Gaussian process regression is particularly effective at predicting chronological age from neuroimaging data which permits the calculation of a brain age gap estimate (brain-AGE). Pathological biological processes such as chronic pain can influence brain-AGE. Because chronic pain disorders can differ in etiology, severity, pain frequency, and sex-linked prevalence, we hypothesize that the expression of brain-AGE may be pain specific and differ between discrete chronic pain disorders. We built a machine learning model using T1-weighted anatomical MRI from 812 healthy controls to extract brain-AGE for 45 trigeminal neuralgia (TN), 52 osteoarthritis (OA), and 50 chronic low back pain (BP) subjects. False discovery rate corrected Welch t tests were conducted to detect significant differences in brain-AGE between each discrete pain cohort and age-matched and sex-matched controls. Trigeminal neuralgia and OA, but not BP subjects, have significantly larger brain-AGE. Across all 3 pain groups, we observed female-driven elevation in brain-AGE. Furthermore, in TN, a significantly larger brain-AGE is associated with response to Gamma Knife radiosurgery for TN pain and is inversely correlated with the age at diagnosis. As brain-AGE expression differs across distinct pain disorders with a pronounced sex effect for female subjects. Younger women with TN may therefore represent a vulnerable subpopulation requiring expedited chronic pain intervention. To this end, brain-AGE holds promise as an effective biomarker of pain treatment response.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-β (Aβ) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aβ, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENTFamilial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-β 42 (Aβ42)/Aβ40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aβ clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretionin vitroand in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Funder: Core funding from the Wellcome Sanger Institute (Wellcome Trust, No. 206194)., Funder: Wellcome PhD Studentship (Wellcome Trust, No. 206194), Funder: Wellcome Clinical PhD fellowship (Wellcome Trust, No. 206194), Funder: Pathological Society of Great Britain and Ireland; doi: https://doi.org/10.13039/501100000672, Funder: Jean Shank/Pathological Society of Great Britain and Ireland Intermediate Clinical Fellowship(JSPS IF 2019 01), Funder: Finnish Center of Excellence Program 2018–2025, No. 312041, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Core funding from The Pharsalia Trust., APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA.

Objective Common surgical treatments for trigeminal neuralgia (TN) include microvascular decompression (MVD) and percutaneous procedures (glycerol rhizolysis; thermocoagulation; and balloon compression). Although the efficacy of each procedure has been documented, direct comparisons of their relative efficacies for TN are lacking. We aimed to directly compare long-term outcomes after first-time MVD with percutaneous surgery in primary (idiopathic and classical) TN and identify predictors of outcome. Methods We conducted a retrospective analysis of prospectively collected data on 185 patients undergoing MVD and 129 undergoing percutaneous surgery. Procedures were performed by one of two neurosurgeons in a single centre; an independent observer collected long-term follow-up data by interviews, using the same outcome measures for all procedures. Results MVD patients were younger than those undergoing percutaneous surgery (P P P =.04), including minor and transient complications. Kaplan-Meier analysis demonstrated that MVD provided longer pain relief than percutaneous procedures (P P =.03 and .01, respectively). Conclusions MVD provides better initial pain relief and longer durability of relief than percutaneous surgery, although carrying a small risk of major complications. Amongst percutaneous procedures, balloon compression gave the most durable relief from pain. Older age and post-operative numbness were predictors of good outcome from percutaneous surgery. These results can help clinicians to counsel patients with primary TN on neurosurgical treatment selection for pain relief.

Nariman Shahid,1,2 Alia Erum,1 Muhammad Zaman,3 Ume Ruqia Tulain,1 Qurat-ul-ain Shoaib,3 Abdul Majeed,4 Muhammad F Rasool,4 Imran Imran,5 Sultan Alshehri,6 Behnam Noorani,7 Faleh Alqahtani8 1College of Pharmacy, University of Sargodha, Sargodha, 40100, Pakistan; 2Akhtar Saeed College of Pharmaceutical Sciences, Lahore, 53720, Pakistan; 3Faculty of Pharmacy, University of Central Punjab, Lahore, 54782, Pakistan; 4Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, 60800, Pakistan; 5Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, 60800, Pakistan; 6Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia; 7Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA; 8Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi ArabiaCorrespondence: Muhammad Zaman; Faleh Alqahtani Email dr.mzaman@ucp.edu.pk; afaleh@ksu.edu.saBackground: Ticagrelor (TG), an antiplatelet drug is employed to treat patients with acute coronary syndrome, but its inadequate oral bioavailability due to poor solubility and low permeability restricts its effectiveness.Purpose: This contemporary work was aimed to design a novel pH-sensitive nanocomposite hydrogel (NCH) formulation incorporating thiolated chitosan (TCH) based nanoparticles (NPs) of Ticagrelor (TG), to enhance its oral bioavailability for effectively inhibiting platelet aggregation.Methods: NCHs were prepared by free radical polymerization technique, using variable concentrations of chitosan (CH) as biodegradable polymer, acrylic acid (AA) as a monomer, N,N-methylene bisacrylamide (MBAA) as cross-linker, and potassium persulphate (KPS) as initiator.Results: The optimum hydrogel formulation was selected for fabricating NCHs, considering porosity, sol-gel fraction, swelling studies, drug loading capacity, and TG’s in vitro release as determining factors. Outcomes of the studies have shown that the extent of hydrogel swelling and drug release was comparatively greater at higher pH (7.4). Moreover, an amplifying trend was observed for drug loading and hydrogel swelling by increasing AA content, while it declined by increasing MBAA. The NCHs were evaluated by various physicochemical techniques and the selected formulation was subjected to in vivo bioavailability studies, confirming enhancement of bioavailability as indicated by prolonged half-life and multifold increase in area under the curve (AUC) as compared to pure TG.Conclusion: The results suggest that NCHs demonstrated a pH-responsive, controlled behavior along with enhanced bioavailability. Thus NCHs can be effectively utilized as efficient delivery systems for oral delivery of TG to reduce the risk of myocardial infarction.Keywords: nanocomposite, thiolated chitosan, biodegradable, bioavailability, free radical polymerization

Background Somatic copy number alterations (SCNAs) are an important class of genomic alteration in cancer. They are frequently observed in cancer samples, with studies showing that, on average, SCNAs affect 34% of a cancer cell’s genome. Furthermore, SCNAs have been shown to be major drivers of tumour development and have been associated with response to therapy and prognosis. Large-scale cancer genome studies suggest that tumours are driven by somatic copy number alterations (SCNAs) or single-nucleotide variants (SNVs). Despite the frequency of SCNAs and their clinical relevance, the use of genomics assays in the clinic is biased towards targeted gene panels, which identify SNVs but provide limited scope to detect SCNAs throughout the genome. There is a need for a comparably low-cost and simple method for high-resolution SCNA profiling. Results We present conliga, a fully probabilistic method that infers SCNA profiles from a low-cost, simple, and clinically-relevant assay (FAST-SeqS). When applied to 11 high-purity oesophageal adenocarcinoma samples, we obtain good agreement (Spearman’s rank correlation coefficient, rs=0.94) between conliga’s inferred SCNA profiles using FAST-SeqS data (approximately £14 per sample) and those inferred by ASCAT using high-coverage WGS (gold-standard). We find that conliga outperforms CNVkit (rs=0.89), also applied to FAST-SeqS data, and is comparable to QDNAseq (rs=0.96) applied to low-coverage WGS, which is approximately four-fold more expensive, more laborious and less clinically-relevant. By performing an in silico dilution series experiment, we find that conliga is particularly suited to detecting SCNAs in low tumour purity samples. At two million reads per sample, conliga is able to detect SCNAs in all nine samples at 3% tumour purity and as low as 0.5% purity in one sample. Crucially, we show that conliga’s hidden state information can be used to decide when a sample is abnormal or normal, whereas CNVkit and QDNAseq cannot provide this critical information. Conclusions We show that conliga provides high-resolution SCNA profiles using a convenient, low-cost assay. We believe conliga makes FAST-SeqS a more clinically valuable assay as well as a useful research tool, enabling inexpensive and fast copy number profiling of pre-malignant and cancer samples.

Glioblastoma evolution is facilitated by intratumour heterogeneity, which poses a major hurdle to effective treatment. Evidence indicates a key role for oncogene amplification on extrachromosomal DNA (ecDNA) in accelerating tumour evolution and thus resistance to treatment, particularly in glioblastomas. Oncogenes contained within ecDNA can reach high copy numbers and expression levels, and their unequal segregation can result in more rapid copy number changes in response to therapy than is possible through natural selection of intrachromosomal genomic loci. Notably, targeted therapies inhibiting oncogenic pathways have failed to improve glioblastoma outcomes. In this Perspective, we outline reasons for this disappointing lack of clinical translation and present the emerging evidence implicating ecDNA as an important driver of tumour evolution. Furthermore, we suggest that through detection of ecDNA, patient selection for clinical trials of novel agents can be optimized to include those most likely to benefit based on current understanding of resistance mechanisms. We discuss the challenges to successful translation of this approach, including accurate detection of ecDNA in tumour tissue with novel technologies, development of faithful preclinical models for predicting the efficacy of novel agents in the presence of ecDNA oncogenes, and understanding the mechanisms of ecDNA formation during cancer evolution and how they could be attenuated therapeutically. Finally, we evaluate the feasibility of routine ecDNA characterization in the clinic and how this process could be integrated with other methods of molecular stratification to maximize the potential for clinical translation of precision medicines.

The preparation of two polyarginine conjugates of the complex Os(II) [bis-(4′-(4-carboxyphenyl)-2,2′:6′,2″-terpyridine)] [Os-(Rn)2]x+ (n = 4 and 8; x = 10 and 18) is reported, to explore whether the R8 peptide sequence that promotes cell uptake requires a contiguous amino acid sequence for membrane permeation or if this can be accomplished in a linearly bridged structure with the additive effect of shorter peptide sequences. The conjugates exhibit NIR emission centered at 754 nm and essentially oxygen-insensitive emission with a lifetime of 89 ns in phosphate-buffered saline. The uptake, distribution, and cytotoxicity of the parent complex and peptide derivatives were compared in 2D cell monolayers and a three-dimensional (3D) multicellular tumor spheroid (MCTS) model. Whereas, the bis-octaarginine sequences were impermeable to cells and spheroids, and the bis-tetraarginine conjugate showed excellent cellular uptake and accumulation in two 2D monolayer cell lines and remarkable in-depth penetration of 3D MCTSs of pancreatic cancer cells. Overall, the data indicates that cell permeability can be promoted via non-contiguous sequences of arginine residues bridged across the metal centre., In achiral Os(II) bisterpyridinyl complexes conjugated to polyarginine the peptide promoted cell permeability can be promoted via non-contiguous sequences of arginine residues bridged across the metal center.

BACKGROUND: We assessed treatment uptake and completion for 6 months of isoniazid (6H) and 3 months of isoniazid plus rifapentine weekly (3HP) in a programmatic setting in Pakistan.METHODS: All household contacts were clinically evaluated to rule out TB disease. 6H was used for TB preventive treatment (TPT) from October 2016 to April 2017; from May to September 2017, 3HP was used for contacts aged ≥2 years. We compared clinical evaluation, TPT uptake and completion rates between contacts aged ≥2 years in the 6H period and in the 3HP period.RESULTS: We identified 3,442 contacts for the 6H regimen. After clinical evaluation, 744/1,036 (72%) started treatment, while 46% completed treatment. In contrast, 3,722 contacts were identified for 3HP. After clinical evaluation, 990/1,366 (72%) started treatment, while 67% completed treatment. Uptake of TPT did not differ significantly between the 6H and 3HP groups (OR 1.03, 95%CI 0.86–1.24). However, people who initiated 3HP had 2.3 times greater odds (95% CI 1.9–2.8) of completing treatment than those who initiated 6H after adjusting for age and sex.CONCLUSION: In programmatic settings in a high-burden country, household contacts of all ages were more likely to complete TPT with shorter weekly regimens, although treatment uptake rate for the two regimens was similar.

The ward round has traditionally been a learning activity in medical education. Apart from education, ward rounds have multiple roles including patient care and communication. Some studies have described the ward round as an ideal place to learn patient management while others reported that little learning happens on rounds due to lack of time and patient volume. This study aimed to develop a deeper understanding of ward round learning from the perspective of postgraduate trainees. A constructivist grounded theory approach was used and data was collected during focus group discussions. Data were analyzed by initial coding, then grouped into focused codes and development of a theoretical framework by the process of constant comparison. Six categories evolved which contributed to the framework. Postgraduate trainees perceive the ward round as an important space where they use different learning activities to acquire knowledge, attitude and skills required of a specialist doctor. They progress from novices to experts under supervision of faculty who lead ward rounds. The round can achieve its full learning potential if planned and organized well but can become a missed opportunity if the learning environment is unfriendly. Patient- and learner-related barriers exist that hinder ward round learning. The framework explains how ward round learning occurs in postgraduate medical education from a trainee perspective. The findings can guide interventions to improve the learning experience. Studies comparing perspectives of teachers to those of learners are needed to further understand the complex learning milieu of the ward round.

Background Primary congenital glaucoma (PCG) is a heterogeneous rare recessively inherited disorder prevalent in regions with high consanguinity. Disease phenotype is associated with increased intra ocular pressure and is a major cause of childhood blindness. Sequence variations in Cytochrome P450 1B1 (CYP1B1) gene are a major cause of PCG. Current study was conducted to screen CYP1B1 gene in highly consanguineous PCG affected families from Pakistani population consistent with the autosomal recessive pattern of PCG inheritance. Methods For this study, patients and controls (clinically unaffected individuals of each family) from 25 consanguineous families belonging to Punjab, Baluchistan and Khyber Pakhtunkhwa, Pakistan were recruited through ophthalmologists. DNA was isolated from collected blood samples. Genetic screening of CYP1B1 gene was done for all enrolled families. In-silico analysis was performed to identify and predict the potential disease-causing variations. Results Pathogenicity screening revealed sequence variants segregating with disease phenotype in homozygous or compound heterozygous form in eleven out of 25 analyzed families. We identified a total of sixteen disease causing variants among which five frameshift i.e., c.629dup (p.Gly211Argfs*13), c.287dup (p.Leu97Alafs*127), c.662dup (p.Arg222Profs*2), c.758_759insA (p.Val254Glyfs*73) and c.789dup (p.Leu264Alafs*63), two silent c.1314G>A, c.771T>G and six missense variations c.457C>G (p.Arg153Gly), c.516C>A (p.Ser172Arg), c.722T>A (p.Val241Glu), c.740T>A (p.Leu247Gln), c.1263T>A (p.Phe421Leu), and c.724G>C (p.Asp242His) are previously un reported. However two frameshift c.868dup (p.Arg290Profs*37), c.247del (p.Asp83Thrfs*12) and one missense variant c.732G>A (p.Met244Ile), is previously reported. Furthermore, six polymorphisms c.1347T>C, c.2244_2245insT, c.355G>T, c.1294G>C, c.1358A>G and c.142C>G were also identified. In the intronic region, a novel silent polymorphism i.e., g.35710_35711insT was found in homozygous state. All the newly detected disease-causing variants were negative in 96 ethnically matched controls. Conclusion Among twenty-five screened families, eight families (PCG50, 52–54, 58, 59, 63 and 67) were segregating disease causing variants in recessive manner. Two families (PCG049 and PCG062) had compound heterozygosity. Our data confirms genetic heterogeneity of PCG in Pakistani population however we did not find molecular variants segregating with PCG in fifteen families in coding exons and intron-exon boundaries of CYP1B1 gene. Genetic counseling was provided to families to refrain from practicing consanguinity and perform premarital screening as a PCG control measure in upcoming generations.

Traditional in vitro models can replicate many essential features of drug transport/permeability across the blood-brain barrier (BBB) but are not entirely projecting in vivo central nervous system (CNS) uptake. Species differences fail to translate experimental therapeutics from the research laboratory to the clinic. Improved in vitro modeling of human BBB is vital for both CNS drug discovery and delivery. High-end human BBB models fabricated by microfluidic technologies offer some solutions to this problem. BBB's complex physiological microenvironment has been established by increasing device complexity in terms of multiple cells, dynamic conditions, and 3D designs. It is now possible to predict the therapeutic effects of a candidate drug and identify new druggable targets by studying multicellular interactions using the advanced in vitro BBB models. This chapter reviews the current as well as an ideal in vitro model of the BBB.

Congenital cataract is causing one-third of blindness worldwide. Congenital cataract is heterogeneous in its inheritance patterns. The current study is aimed to explore the unknown genetic causes underlying congenital cataracts.Blood samples from affected and normal individuals of n = 25 Pakistani families identified with congenital cataracts were collected. Genomic DNA was extracted and Sanger sequencing was performed to identify novel pathogenic variants in the FYCO1 (MIM#607182) gene. Later structural bioinformatics tools and molecular dynamics simulations were performed to analyze the impact of these variants on protein structure and function.Sanger sequencing resulted in the identification of a novel splice site mutation (NM_024513.3: c.3151-29_3151-7del) segregating in an autosomal recessive manner. This novel variant was confirmed to be absent in the n = 300 population controls. Further, bioinformatics tools revealed the formation of a mutant protein with a loss of the Znf domain. In addition, we also found a previously known (c.4127 T C; p.Leu1376Pro) mutation in four families. We also report a novel heterozygous variant (c.3419G A; p.Arg1140Gln) in another family.In conclusion, we report a novel deletion (NM_024513.3: c.3151-29_3151-7del) in one family and a frequent homozygous missense mutation (c.4127 T C; p.Leu1376Pro) in four Pakistani families. The current research highlights the importance of autophagy in lens development and maintaining its transparency.

Background Adequate knowledge of root canal morphology and possible variations is essential to achieve perfect root canal treatment and overcome treatment failure. Appropriate knowledge on root and canal morphology, communication, and documentation amongst dentists will be challenging from a diagnostic and successful treatment point of view. Methods A total of 3420 samples were included in this study from 285 cone-beam computed tomography images of the Saudi residents, including 171 males and 114 females aged 15 to 68 years from retrospective data dated from January 2018 to April 2021. The images were examined in sagittal, axial and coronal views using a 3D version software 1.0.10.6388. The number of canal and canal morphology was recorded using Vertucci and the new classification system. The SPSS 26 was used to conduct the statistical analysis as descriptive statistics such as mean; standard deviation and frequency were calculated. The Chi-square test analysed the data with the significance level set at 0.05. Results A total of 285 subjects participated in the study. Majority of the participants were Saudi nationals (80.7%), followed by Indian (7.4%), Pakistani (4.2%) and other nationalities. According to Vertucci and the new classification system, Type I and 1TN1 were the most common types, followed by Type III and Type IV, and then 1TN1-2-1 and 1TN1-2 in mandibular anteriors. The prevalence of canal variations in mandibular canine was higher in females than in males (P = 0.002). Maxillary laterals and mandibular anteriors showed the significant difference in the prevalence of root canal variation in relation to the ethnicity (P = 0.001) and age of the patients. Younger patients showed more variations than the older patients (P = 0.012, P = 0.023, P = 0.001, P = 0.001) in terms of maxillary laterals, mandibular central, laterals and canines, respectively. Conclusion Mandibular permanent anteriors showed a wide range of canal variations and canal complexity. Males and females did not demonstrate a wide range of variation in the root canal morphology except for the canines in relation to the gender of the patients.

Introduction Internal neurolysis (INL) is a surgical procedure where trigeminal nerve fibres are separated between the pons and porus trigeminus to relieve trigeminal neuralgia (TN). We report pain and functional outcomes to evaluate its safety and efficacy. Materials and methods Prospective cohort of all patients undergoing retrosigmoid craniotomy and INL between 2015 and 2017 at University Hospital Southampton. Patients with type I (6) or type II (2) refractory TN and no clear neurovascular conflict were offered INL as an alternative to partial sensory rhizotomy. Barrow Pain Intensity Scale (BNI) and Brief Pain Inventory Facial scores (BPI-Facial) were assessed. Minimum follow-up was 2 years'. Results Eight patients (7F:1M) underwent INL. Two had MS. Pre-operatively, all had severe pain (BNI grade V) and the median BPI-Facial score was 115 (range 79-123).. There were no unexpected complications. On last follow-up, six (75%) had no pain (BNI grade I), while two (25%) had recurred (at 5 and 27 months). Median BPI-Facial score for all patients on the last follow-up was 20 (range 18-91) reflecting dramatically improved quality of life and activities. Conclusions INL is a potentially safe and effective treatment for refractory TN. Long-term efficacy is unknown, but early results are promising.

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

Prognostication in oesophageal cancer on the basis of preoperative variables is challenging. Many of the accepted predictors of survival are only derived after surgical treatment and may be influenced by neoadjuvant therapy. This study aims to explore the relationship between pre-treatment endoscopic tumour morphology and postoperative survival.Patients with endoscopic descriptions of tumours were identified from the prospectively managed databases including the OCCAMS database. Tumours were classified as exophytic, ulcerating or stenosing. Kaplan Meier survival analysis and multivariable Cox regression analyses were performed to determine hazard ratios (HR) with 95% confidence intervals.262 patients with oesophageal adenocarcinoma undergoing potentially curative resection were pooled from St Thomas' Hospital (161) and the OCCAMS database (101). There were 70 ulcerating, 114 exophytic and 78 stenosing oesophageal adenocarcinomas. Initial tumour staging was similar across all groups (T3/4 tumours 71.4%, 70.2%, 74.4%). Median survival was 55 months, 51 months and 36 months respectively (p 0.001). Rates of lymphovascular invasion (P = 0.0176), pathological nodal status (P = 0.0195) and pathological T stage (P = 0.0007) increased from ulcerating to exophytic to stenosing lesions. Resection margin positivity was 21.4% in ulcerating tumours compared to 54% in stenosing tumours (p 0.001). When compared to stenosing lesions, exophytic and ulcerating lesions demonstrated a significant survival advantage on multivariable analysis (HR 0.56 95% CI 0.31-0.93, HR 0.42 95% CI 0.21-0.82).This study demonstrates that endoscopic morphology may be an important pre-treatment prognostic factor in oesophageal cancer. Ulcerating, exophytic and stenosing tumours may represent different pathological processes and tumour biology.

The blood–brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain’s metabolic activity as well as neuronal function. Thus, the functional and structural integrity of the BBB is pivotal to maintain the homeostasis of the brain microenvironment. The different cells and structures contributing to developing this barrier are summarized along with the different functions that BBB plays at the brain–blood interface. We also explained the role of shear stress in maintaining BBB integrity. Furthermore, we elaborated on the clinical aspects that correlate between BBB disruption and different neurological and pathological conditions. Finally, we discussed several biomarkers that can help to assess the BBB permeability and integrity in-vitro or in-vivo and briefly explain their advantages and disadvantages.

Background and aims The consumption of alcohol is prohibited in Iran; however, concerns regarding alcohol-related harm have led to the development of national policies supporting the establishment of officially endorsed alcohol treatment settings. As a part of these policies, the Iranian Ministry of Health supported the establishment of the first alcohol withdrawal management unit in the psychosomatic unit of Taleghani Hospital in 2015. The purpose of this study is to report on this pilot project. Methods This was an observational and descriptive study, conducted on 83 patients with alcohol use disorder based on DSM 5 who were consecutively admitted to the unit for alcohol withdrawal management, from March 2017 to March 2018. The demographic data, alcohol use history, comorbid physical and psychiatric conditions, completion of inpatient treatment, length of hospital stay, and adverse events were extracted from the patients’ records using a checklist developed by the authors. Results 95.2% of the patients were male. The mean age was 45.3 (±12.2) years. Study participants reported using 38.7 (±29.6) standard drinks in a drinking day during the last year. Mean length of stay was 9.01 (±6.8) days. 81.7% of patients completed the inpatient treatment episode. Six patients (7.2%) had a complicated withdrawal (delirium), and no incidents of a withdrawal seizure were reported during the period of this study. Conclusions This is the first study providing preliminary results on the safety and effectiveness of symptom-triggered alcohol withdrawal management in Iran. The clinical and policy level implications of these findings have been discussed.

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 10(9)/L (range, 0.01–2.75 X 10(9)/L) and was significantly higher in patients who achieved complete response (p=0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2–0.8, p=0.007). Low DLIx was independently associated with shorter progression-free (p=0.02) and overall survival (p=0.02). DLIx was associated with genetic variations related to drug metabolism and macrophage biology such as ABCB1, MISP and CPVL. The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.

There is a paucity of information concerning vital pulp treatment outcomes in the undergraduate teaching setting. This study aimed to determine which type of deciduous molar, arch location, type of vital pulp therapy, and the number of carious surfaces involved had a better prognosis when carried out by undergraduate dental students. The method used was the review of clinical records of 590 patients with 600 deciduous molars, that visited the outpatient undergraduate dental clinics for vital pulp therapy. Statistical analysis used to determine the associations of tooth type, arch location, treatment type, and the number of carious surfaces involved in successful outcomes was logistic regression analysis with significance set at p &lt, 0.05. According to the regression analysis model results, there was a significant association based on tooth type (p &lt, 0.05) and arch location (p = 0.003). In addition, there was a significant association based on the type of treatment performed (p = 0.036). However, there was no significant association in success rates based on the number of carious surfaces involved (p = 0.873). In conclusion, second deciduous molars and maxillary deciduous molars had a better overall prognosis, and indirect pulp therapy was revealed to be more highly associated with successful treatment outcomes in comparison to ferric sulfate pulpotomy in our setting.

Violent victimization and substance use are higher among sexual minority cisgender women (SMCW) than heterosexual cisgender women. Unknown, however, is how polyvictimization-experiencing multiple types of violent victimization-affects substance use among SMCW.

The recent renaissance of psychedelic science has reignited interest in the similarity of drug-induced experiences to those more commonly observed in psychiatric contexts such as the schizophrenia-spectrum. This report from a multidisciplinary working group of the International Consortium on Hallucinations Research (ICHR) addresses this issue, putting special emphasis on hallucinatory experiences. We review evidence collected at different scales of understanding, from pharmacology to brain-imaging, phenomenology and anthropology, highlighting similarities and differences between hallucinations under psychedelics and in the schizophrenia-spectrum disorders. Finally, we attempt to integrate these findings using computational approaches and conclude with recommendations for future research.

A significant proportion of patients infected with the novel coronavirus, now termed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), require intensive care admission and subsequent mechanical ventilation. Pneumothorax, a potential fatal complication of mechanical ventilation, can further complicate the management of COVID-19 patients, whilst chest drain insertion may increase the risk of transmission of attending staff. We present a case series and a suggested best-practice protocol for how to manage and treat pneumothoraces in COVID-19 patients in an intensive care unit setting.

Background Glioma is the most common intrinsic brain tumor and also occurs in the spinal cord. Activating EGFR mutations are common in IDH1 wild-type gliomas. However, the cooperative partners of EGFR driving gliomagenesis remain poorly understood. Results We explore EGFR-mutant glioma evolution in conditional mutant mice by whole-exome sequencing, transposon mutagenesis forward genetic screening, and transcriptomics. We show mutant EGFR is sufficient to initiate gliomagenesis in vivo, both in the brain and spinal cord. We identify significantly recurrent somatic alterations in these gliomas including mutant EGFR amplifications and Sub1, Trp53, and Tead2 loss-of-function mutations. Comprehensive functional characterization of 96 gliomas by genome-wide piggyBac insertional mutagenesis in vivo identifies 281 known and novel EGFR-cooperating driver genes, including Cdkn2a, Nf1, Spred1, and Nav3. Transcriptomics confirms transposon-mediated effects on expression of these genes. We validate the clinical relevance of new putative tumor suppressors by showing these are frequently altered in patients’ gliomas, with prognostic implications. We discover shared and distinct driver mutations in brain and spinal gliomas and confirm in vivo differential tumor suppressive effects of Pten between these tumors. Functional validation with CRISPR-Cas9-induced mutations in novel genes Tead2, Spred1, and Nav3 demonstrates heightened EGFRvIII-glioma cell proliferation. Chemogenomic analysis of mutated glioma genes reveals potential drug targets, with several investigational drugs showing efficacy in vitro. Conclusion Our work elucidates functional driver landscapes of EGFR-mutant gliomas, uncovering potential therapeutic strategies, and provides new tools for functional interrogation of gliomagenesis.

Adolescents with single ventricle heart disease (SVHD) exhibit mood and cognitive deficits, which may result from injury to the basal ganglia structures, including the caudate nuclei. However, the integrity of the caudate in SVHD adolescents is unclear. Our aim was to examine the global and regional caudate volumes, and evaluate the relationships between caudate volumes and cognitive and mood scores in SVHD and healthy adolescents. We acquired two high-resolution T1-weighted images from 23 SVHD and 37 controls using a 3.0-Tesla MRI scanner, as well as assessed mood (Patient Health Questionnaire-9 [PHQ-9]; Beck Anxiety Inventory [BAI]) and cognition (Montreal Cognitive Assessment [MoCA]; Wide Range Assessment of Memory and Learning–2; General Memory Index [GMI]) functions. Both left and right caudate nuclei were outlined, which were then used to calculate and compare volumes between groups using ANCOVA (covariates: age, gender, and head-size), as well as perform 3D surface morphometry. Partial correlations (covariates: age, gender, and head-size) were used to examine associations between caudate volumes, cognition, and mood scores in SVHD and controls. SVHD subjects showed significantly higher PHQ-9 and BAI scores, indicating more depressive and anxiety symptoms, as well as reduced GMI scores, suggesting impaired cognition, compared to controls. SVHD patients showed significantly reduced caudate volumes (left, 3,198.8 ± 490.1 vs. 3,605.0 ± 480.4 mm(3), p < 0.004; right, 3,162.1 ± 475.4 vs. 3,504.8 ± 465.9 mm(3), p < 0.011) over controls, and changes were localized in the rostral, mid-dorsolateral, and caudal areas. Significant negative correlations emerged between caudate volumes with PHQ-9 and BAI scores and positive correlations with GMI and MoCA scores in SVHD and controls. SVHD adolescents show significantly reduced caudate volumes, especially in sites that have projections to regulate mood and cognition, which may result from developmental and/or hypoxia-/ischemia-induced processes.

PURPOSE: We aimed to evaluate the efficacy and safety of use of the Fasting Algorithm for Singaporeans with Type 2 Diabetes (FAST) during Ramadan. METHODS: We performed a prospective, multicenter, randomized controlled trial. The inclusion criteria were age ≥21 years, baseline glycated hemoglobin (HbA(1c)) level ≤9.5%, and intention to fast for ≥10 days during Ramadan. Exclusion criteria included baseline estimated glomerular filtration rate

Purpose: Transgender and nonbinary (trans*) people are affected disproportionately by discrimination and violence, contributing to gender minority stress and negative health effects. Transgender community connection (TCC), defined as (i) emotional connectedness (internal sense of belonging) to the trans* community and/or (ii) behavioral participation in the trans* community (observable interaction with other trans* people, in person, online, or through media) may moderate these negative effects on health. This systematic review synthesizes research on links between TCC and health and wellbeing for trans* people. Methods: Twenty research articles (3 quantitative, 3 mixed methods, and 14 qualitative) linking TCC to health and wellbeing were identified from systematic searches of PubMed, CINAHL, and PsycINFO. Data regarding TCC were extracted, synthesized, and grouped by (i) gender transitioning, (ii) mental health, (iii) sexual health, and (iv) access to care to illustrate the findings. Results: TCC was linked to several positive outcomes, including improved mental health, increased connection to care, supported exploration of sexual and gender identities, and informed gender transition. For transgender women, especially, TCC was also linked to increased engagement in sex work (as a worker, not a client) and, in some cases, deterred them from getting sexual health testing and treatment due to fear of being observed at specialized clinics and subsequent loss of confidentiality among peers. Conclusion: These findings highlight the overall protective nature of TCC and a need to consider best practices to ensure confidentiality for community members. The findings can be used to inform the development and adaptation of health care interventions aimed at decreasing the harmful effects of gender minority stress for trans* people.

Limited data exist regarding the outcome of patients with follicular lymphoma (FL) who relapse or progress after frontline lenalidomide and rituximab (R2). Moreover, mechanisms of resistance to R2 in FL remain unclear, with increased protumoral macrophages suspected as a major contributory culprit to this phenomenon. This retrospective study analyzed the outcome of patients with advanced-stage FL grade 1 to 3A who relapsed or progressed after frontline R2. A multiplex immunofluorescence macrophage panel, including CD47, CD14, CD68, CD115 (also known as colony-stimulating factor 1 receptor [CSF1R]), CD163, CD172a (also known as signal regulatory protein α [SIRPα]), and CD274 (also known as programmed cell death-ligand 1 [PDL1]), was used to stain tissue biopsy specimens collected before initiation of R2 and at the time of progression. Among 156 patients with advanced-stage FL treated with frontline R2, 33 (21%) relapsed or progressed and required second-line therapy, after a median of 33 months (range, 1-122 months). Second-line therapy was chemoimmunotherapy in 16 (48%) patients and other therapy in 17 (52%). The overall response rate was 78%, and complete response rate was 72%. Median progression-free survival was significantly longer in patients who received chemoimmunotherapy compared with other therapy (99 vs 25 months; P = .004). Three macrophage populations were significantly increased in tissue samples collected at progression compared with before frontline treatment: CD68+CD115+ (P = .02), CD68+CD115+CD172a+ (P = .02), and CD68+CD163+CD172a+ (P = .01). Chemoimmunotherapy is an effective treatment strategy for patients with FL who relapse after frontline R2. Therapies targeting specific macrophage populations may yield novel approaches for improving outcomes with frontline R2.

Background. The caries preventive effect of Colgate Duraphat® and GC Tooth Mousse Plus® has been widely studied, but the remineralisation potential of initial occlusal caries using these two remineralisation materials remains unclear. Aim. This study is aimed at evaluating and comparing the remineralisation of early enamel caries on the occlusal surface of permanent posterior teeth using ICDAS II caries scoring system and DIAGNOdent Pen (DDPen) after remineralisation with Colgate Duraphat® and GC Tooth Mousse Plus®. Materials and Methods. Extracted posterior teeth ( N = 120 ) with incipient occlusal caries were included in this study. The occlusal surface of each tooth was scored using DDPen and ICDAS II scoring before remineralisation. Then, remineralisation of the teeth of the experimental group was carried out using either CPP-ACP-F or fluoride varnish. After the remineralisation procedures, the occlusal surface of each tooth was again scored using DDPen and ICDAS II scoring. The teeth were then fixed in dental stone blocks and sectioned longitudinally for histological examination using a stereomicroscope. Statistical analysis was performed to calculate the sensitivity and specificity of DDPen and ICDAS II to detect remineralisation and compare with the gold standard histological examination. Results. According to ICDAS-II scores, a significant difference was noted in GC Tooth Mousse Plus® and Duraphat® study samples, whereas the difference between the pre-and post-remineralisation of the control group was not significant. According to the DDPen score criteria, a statistically significant difference was noted among all study groups; however, a greater significance level was noted in the GC Tooth Mousse Plus® and Duraphat® study samples compared with the control group. The Spearman’s rank correlation of ICDAS-II and DDPen with Downer’s histological score (gold standard) revealed a higher association of DDPen score (.738) as compared to ICDAS-II scores (.430). Conclusion. The study concluded that both ICDAS II and DDPen could detect remineralisation of early enamel occlusal caries. DDPen was more sensitive than ICDAS-II to detect remineralisation compared with the Downers histological scores.

OBJECTIVE To provide the first comprehensive analysis of the Twitterverse amongst academic urologists and programmes in North America. METHODS Using national accreditation and individual programme websites, all active urology residency programmes (USA and Canada) and academic Urology faculty at these programmes were identified. Demographic data for each programme American Urological Association [AUA] section, resident class size) and physician (title, fellowship training, Scopus Hirsch index [H-index] and citations) were documented. Twitter metrics (Twitter handle, date joined, # tweets, # followers, # following, likes) for programmes and physicians were catalogued (data capture: March-April 2019). Descriptive analyses and temporal trends in Twitter utilisation amongst programmes and physicians were assessed. Multivariable logistic regression was used to identify predictors of Twitter use. RESULTS In all, 156 academic programmes (143 USA, 13 Canada) and 2214 academic faculty (2015 USA, 199 Canada) were identified. Twitter utilisation is currently 49.3% and 34.1% amongst programmes and physicians, respectively, and continues to increase. On multivariable analysis, programmes with 3-5 residents/year and programmes with a higher percentage of faculty Twitter engagement were more likely to have Twitter accounts. From a physician perspective, those with fellowship training, lower academic rank (Clinical Instructor, Assistant Professor, Associate Professor vs Professor) and higher H-indices were more likely to have individual Twitter accounts. CONCLUSION There is a steady increase in Twitter engagement amongst Urology programmes and academic physicians. Faculty Twitter utilisation is an important driver of programme Twitter engagement. Twitter social media activity is strongly associated with academic productivity, and may in fact drive academic metrics. Within Urology, social media presence appears to be proportional to academic activity.

Purpose: To evaluate the outcome of trabeculectomy augmented with mitomycin C in primary congenital glaucoma and to document the complications of the procedure in young children. Methods: This was a prospective study of children younger than 2 years with primary congenital glaucoma who were treated with primary trabeculectomy with mitomycin C. After surgery, patients were observed for a minimum of 1 year. Trabeculectomy success was defined as an intraocular pressure (IOP) of 21 mm Hg or less without (absolute success) or with (qualified success) topical antiglaucoma medications. Surgical success was assessed at 1, 6, and 12 months after the procedure. Results: Seventy-four eyes of 42 children were included in the current study. The mean age was 11.7 ± 8.5 months. Of the 42 children, 57.2% were male and 42.8% were female. The mean IOP after surgery was significantly lower than the preoperative IOP ( P < .0001). Absolute success was observed in 98.6%, 50%, and 27% of eyes at 1, 6, and 12 months, respectively. Qualified success was achieved in 1.4%, 36.5%, and 48.6% of eyes at 1, 6, and 12 months, respectively. Overall success of the procedure was 100% at 1 month but reduced to 86.5% at 6 months and 75.7% at 12 months. In 24.3% of eyes, IOP was not controlled even with adjunctive topical glaucoma medications and was considered a failure. Postoperative complications were shallow anterior chamber (10.8%), collapsed anterior chamber (1.3%), and choroidal detachment (12.0%). Complications were managed conservatively, and 6 eyes needed surgical intervention. Conclusions: Augmented trabeculectomy is a useful primary procedure in children with primary congenital glaucoma. Topical glaucoma medications supplement the success of the procedure. [ J Pediatr Ophthalmol Strabismus . 2022;59(3):180–186.]

Strabismus (STBMS) is a multifactorial ocular disorder in children that leads to misalignment of the eyes. Insulin-like growth factor 1 (Two hundred seventy-four STBMS cases and 272 unaffected controls were recruited, and their DNA was extracted. TwoMultivariate logistic regression analysis revealed that rs5742632 (odds ratio [95% confidence interval] = 1.05[1.01-1.06], p = 0.03) is associated with STBM. Moreover, rs6214 (1.03[1.01-1.05], p = 0.03) and rs5742632 (1.09[1.04-1.11], p = 0.04) were associated with exotropia. Statistically, no significant difference in

Phthalate esters (PEs) one of the widely used plasticizers, and are known for their environmental contamination and endocrine disruption. Hence, it is important to study their distribution in a riverine environment. This study was aimed to determine the Spatio-temporal trends of 16 PEs in surface water, sediment and fish from rivers in southern India, and to assess their environmental health risks. Phthalates were quantified in all matrices with the mean concentrations (∑

Background. Citation analysis has emerged to play a significant role in recognition of the most useful areas of research. Endodontic microbiology has been a topic of interest for endodontists as well as periodontists and oral surgeons. This bibliometric analysis is aimed at identifying and reporting the characteristics of the top 50 cited articles on endodontic microbiology. Methods. The articles were identified through a search on Web of Science (WoS), property of Clarivate Analytics database published on endodontic microbiology. The citation information of the selected articles was recorded. The Journal of Endodontics, International Endodontic Journal, Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, Dental Traumatology, and Australian Endodontic Journal were searched in the search title. Descriptive and bivariate analyses were performed using a statistical software package SPSS. Statistical analysis was performed using Shapiro-Wilk, Kruskal-Wallis, Post hoc, Mann-Kendall trend, and Spearman-rank tests. Results. The 50 most cited articles were published from 1965 to 2012 with citation count varying from 1065 to 103 times. The total citation counts of articles recorded were 11,525 (WoS), 12,602 (Elseviers’ Scopus), and 28,871 (Google Scholar). The most prolific years in terms of publications were 2001, 2002, and 2003, with five publications each, followed by 2005 with four. The year with most citations was 1998, with 1,330 citations, followed by 1965 and 2001, with 1,065 and 1,015 citations, respectively. A total of 136 authors contributed to the top 50 most cited articles with 27 corresponding institutions from 12 different countries. The most common methodological design was in vitro study, followed by clinic-laboratory study, literature review, systematic review and meta-analysis, and animal study. Conclusions. The present study provided a detailed list of the top 50 most cited and classic articles on microbiology in endodontics. This will help researchers, students, and clinicians in the field of endodontics as an impressive source of information.

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Hypomelanosis of Ito is a rare neurocutaneous syndrome characterized by presence of hypopigmented skin lesions arranged in whorls and streaks following the lines of Blaschko and are often accompanied by abnormalities of the central nervous system, skeletal system, eyes and teeth. Additional symptoms include deafness, hemihypertrophy, cardiac abnormalities, renal malformations, and abnormalities of the genitourinary tract.

Human cancers harbor substantial genetic, epigenetic, and transcriptional changes, only some of which drive oncogenesis at certain times during cancer evolution. Identifying the cancer-driver alterations amongst the vast swathes of “passenger” changes still remains a major challenge. Transposon and CRISPR screens in vivo provide complementary methods for achieving this, and each platform has its own advantages. Here, we review recent major technological breakthroughs made with these two approaches and highlight future directions. We discuss how each genetic screening platform can provide unique insight into cancer evolution, including intra-tumoral heterogeneity, metastasis, and immune evasion, presenting transformative opportunities for targeted therapeutic intervention.

Introduction Kawasaki disease is a common vasculitis of unknown etiology that occurs mainly in preschool children. It manifests as a self-limited acute febrile illness with other features including extremity changes, cervical lymphadenopathy, oropharyngeal changes, truncal rash, and conjunctivitis. Intestinal involvement is not uncommon, with abdominal pain and vomiting being the most frequently reported symptoms. Intussusception has been described as a manifestation or complication of this disease, but few reports exist in literature. Case presentation A 7-month-old boy of Asian origin who presented with vomiting and passage of bloody mucoid stool was diagnosed with intussusception that was successfully reduced during emergency laparotomy. The baby was discharged home post-surgery following clinical improvement. He was readmitted on the fourth postoperative day with fever, irritability, and diarrhea. He was investigated and treated for presumed intraabdominal sepsis with multiple antibiotics with no improvement. He gradually developed the mucocutaneous features of Kawasaki disease and was treated with intravenous immunoglobulin and aspirin with good outcome. Conclusion Intussusception and Kawasaki disease both commonly occur in children less than 2 years old. It is important to include Kawasaki disease as a differential diagnosis in children of this age who present with an acute febrile illness and gastrointestinal symptoms. A common underlying pathologic process could be contributing to both conditions.

Background The blood–brain barrier (BBB) plays a critical role in protecting the central nervous system (CNS) from blood-borne agents and potentially harmful xenobiotics. Our group’s previous data has shown that tobacco smoke (TS) and electronic cigarettes (EC) affect the BBB integrity, increase stroke incidence, and are considered a risk factor for multiple CNS disorders. Metformin was also found to abrogate the adverse effects of TS and EC. Methods We used sucrose and mannitol as paracellular markers to quantitatively assess TS and EC’s impact on the BBB in-vitro. Specifically, we used a quantitative platform to determine the harmful effects of smoking on the BBB and study the protective effect of metformin. Using a transwell system and iPSCs-derived BMECs, we assessed TS and EC’s effect on sucrose and mannitol permeability with and without metformin pre-treatment at different time points. Concurrently, using immunofluorescence (IF) and Western blot (WB) techniques, we evaluated the expression and distribution of tight junction proteins, including ZO-1, occludin, and claudin-5. Results Our data showed that TS and EC negatively affect sucrose and mannitol permeability starting after 6 h and up to 24 h. The loss of barrier integrity was associated with a reduction of TEER values. While the overall expression level of ZO-1 and occludin was not significantly downregulated, the distribution of ZO-1 was altered, and discontinuation patterns were evident through IF imaging. In contrast to occludin, claudin-5 expression was significantly decreased by TS and EC, as demonstrated by WB and IF data. Conclusion In agreement with previous studies, our data showed the metformin could counteract the negative impact of TS and EC on BBB integrity, thus suggesting the possibility of repurposing this drug to afford cerebrovascular protection.

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from preoperative surgical planning to medical device design optimization.

The impact of pre-treatment maximum standardized uptake value (SUVmax) on the outcome of follicular lymphoma (FL) following specific frontline regimens has not been explored. We performed a retrospective analysis of 346 patients with advanced stage follicular lymphoma (FL) without histological evidence of transformation, and analyzed the impact of SUVmax on outcome after frontline therapy. Fifty-two (15%) patients had a SUVmax >18, and a large lymph node ≥6 cm was the only factor associating with SUVmax >18 on multivariate analysis (odds ratio 2.7, 95% confidence interval [CI]: 1.3-5.3, P=0.006). The complete response rate was significantly lower among patients treated with non-anthracycline-based regimens if SUVmax was >18 (45% vs. 92%, P18 was associated with significantly shorter progression-free survival among patients treated with non-anthracycline-based regimens (77 months vs. not reached, P=0.02), but not among patients treated with R-CHOP (P=0.73). SUVmax >18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (8-year OS 70% vs. 90%, P=0.02) and non-anthracycline-based frontline regimens (8-year OS 50% vs. 85%, P=0.001). In conclusion, pre-treatment PET scan has prognostic and predictive value in patients with advanced stage FL receiving frontline treatment.

Clostridium difficile (CD) is the most common cause of nosocomial diarrhea. We aim to highlight practice measures for controlling and preventing Clostridium difficile infections (CDI) in the hospital setting. Electronic databases including PubMed, MEDLINE, Google Scholar, ClinicalTrials.gov, and Cochrane Databases were searched for human studies that assessed strategic measures for the prevention of CDI. Bundled interventions can effectively reduce the rates of CDI. Current evidence support the implementation antibiotic stewardship programs, hygiene enhancement, dietary management with probiotics, use of copper surfaces, and the cautious use of PPIs. However, current guidelines do not advocate the use of copper, probiotics, or the discontinuation of PPIs as a means for reducing CDI. We review these practical and evidence-based approaches.

Cancers occurring at the gastroesophageal junction (GEJ) are classified as predominantly esophageal or gastric, which is often difficult to decipher. We hypothesized that the transcriptomic profile might reveal molecular subgroups which could help to define the tumor origin and behavior beyond anatomical location. The gene expression profiles of 107 treatment‐naïve, intestinal type, gastroesophageal adenocarcinomas were assessed by the Illumina‐HTv4.0 beadchip. Differential gene expression (limma), unsupervised subgroup assignment (mclust) and pathway analysis (gage) were undertaken in R statistical computing and results were related to demographic and clinical parameters. Unsupervised assignment of the gene expression profiles revealed three distinct molecular subgroups, which were not associated with anatomical location, tumor stage or grade (p > 0.05). Group 1 was enriched for pathways involved in cell turnover, Group 2 was enriched for metabolic processes and Group 3 for immune‐response pathways. Patients in group 1 showed the worst overall survival (p = 0.019). Key genes for the three subtypes were confirmed by immunohistochemistry. The newly defined intrinsic subtypes were analyzed in four independent datasets of gastric and esophageal adenocarcinomas with transcriptomic data available (RNAseq data: OCCAMS cohort, n = 158; gene expression arrays: Belfast, n = 63; Singapore, n = 191; Asian Cancer Research Group, n = 300). The subgroups were represented in the independent cohorts and pooled analysis confirmed the prognostic effect of the new subtypes. In conclusion, adenocarcinomas at the GEJ comprise three distinct molecular phenotypes which do not reflect anatomical location but rather inform our understanding of the key pathways expressed., What's new? Adenocarcinomas that arise at the junction between the esophagus and the stomach are currently classified based on location. Here, the authors looked at patterns of gene expression of these cancers. They found that gastro‐esophageal junction adenocarcinomas can be sorted into three biological subtypes, independent of location, based on gene expression. Group 1 cancers have boosted stomach‐specific genes that combat the effects of acid reflux. Group 2 tumors express genes characteristic to the intestinal tract, and the genes active in Group 3 relate to inflammation. The differences in biological pathway expression means that these differences could be used to improve treatment.

Background Balloon compression (BC), thermocoagulation (TC), and glycerol rhizolysis (GR) are percutaneous surgical options for trigeminal neuralgia (TN). Whether the outcomes of these procedures in multiple sclerosis -related TN (MS-TN) are as effective as in idiopathic TN (ITN) is unknown. Objective To retrospectively compare pain relief, complications, and durability achieved by these 3 types of procedures in MS-TN and ITN. Methods Two hundred and four patients with typical TN were treated percutaneously: 33 had MS-TN (64 procedures) and 171 had ITN (329 procedures). All were performed by 1 of 2 neurosurgeons; interviews enabled long-term data to be gathered by an independent observer. Results MS-TN patients (53.1%) had Barrow Neurological Institute pain scores of I or II after a percutaneous procedure, compared with 59.3% in the ITN cohort; there was no difference in initial relief between the 2 groups overall (P = .52). There was a trend toward fewer complications in MS-TN compared with ITN (23.4% vs 33.7%, respectively; P = .058). Kaplan-Meier analysis demonstrated no difference in durability of relief in MS-TN (median 23.0 mo) compared with ITN overall (median 24.0 mo; P = .75). Subgroup analysis demonstrated longer relief from BC and TC compared with GR in MS-TN (P = .013). Multivariate analysis confirmed that although the presence of MS does not predict durability of outcome, postoperative numbness (P = .0046) and undergoing a repeat procedure (P = .037) were significant predictors. Conclusion BC and TC are safe and effective in MS-TN. Postoperative numbness is the strongest prognostic factor in MS-TN.

Traumatic aortic injuries can be a lethal event. Almost 88% of patients with traumatic aortic injuries die within the first hour and only 2% survive long enough to develop a chronic aneurysm. Injury to the ascending aorta, whether acute or chronic, are typically managed with surgery, and those in the descending aorta, are managed conservatively or in some cases with stents. We present a rare case of a 53-year old gentleman with intra-aortic migration of a left clavicular prosthesis used for restoration of the left shoulder girdle.